Sexual transmission of human immunodeficiency type 1 (HIV-1) in humans is characterized by the remarkable ability of the virus to transverse mucosal epithelial barriers and initiate infection of cells in the underlying tissues. Immature dendritic cell subsets present in the peripheral mucosal tissues capture virus particles, migrate to peripheral lymph nodes, mature and help initiate adaptive immune responses against the invading pathogen by interacting with T cells. HIV, in turn, has exploited dendritic cell - T cell interactions for its dissemination in the infected individual. Though HIV particles can be captured by dendritic cell-specific attachment factors such as dendritic cell-specific intercellular adhesion molecule grabbing non-integrin (DC-SIGN), it remains unclear as to how these captured particles are transferred to CD4+ T cells. We propose herein to study the mechanism of dendritic cell mediated HIV-1 transmission to T cells. We will explore the hypothesis that captured virus particles traffic to unique intracellular compartments where HIV is maintained without loss of infectivity, and that during the course of normal dendritic cell - T cell interactions virus particles are released to facilitate robust infections of T cells. The mechanism of cell associated virus transfer will be addressed by the following Specific Aims: 1) To define the nature of intracellular compartment in dendritic cells that harbors infectious virus particles following capture; 2) To explore how HIV accesses this intracellular compartment, specifically following DCSIGN binding and whether the nature of the endocytic pathway that is targeted by virus particle binding to DC-SIGN defines long term infectivity of HIV in dendritic cells; 3) To determine the signals that stimulate the release of internalized HIV to the extracellular milieu. We believe that the studies described in these aims would delineate the role of dendritic cells, and especially DC-SIGN, in the initiation and propagation of HIV-1 infection in vivo.
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